Tissue fibrosis leads to fatal defunctionalization of tissues. For example, liver fibrosis progresses to hepatocirrhosis, liver failure and liver cancer, and fibrosis in kidney ultimately leads to end-stage renal failure. Nevertheless, up to now, there have been no drugs for treating fibrotic diseases, and tissue grafting is the only cure available. The reason that there are no anti-fibrotic drugs is because molecular mechanism of fibrogenesis has not been clearly elucidated.
It is widely accepted that activated stellate cells play a key role in the development of fibrosis of liver and pancreas and that they are primarily responsible for the excessive deposition of extracellular matrix proteins such as collagen. It appears that, in addition to the liver, stellate cells are present in extrahepatic organs such as the pancreas, lung, kidney, intestine, spleen, salivary gland, and eye.
The stellate cells are important in controlling retinoid homeostasis in the whole body. Vitamin A (retinol), acquired from diet, is transferred to the liver and taken up by hepatocytes as a chylomicron remnant. It has been suggested that retinol binding protein (RBP) plays a role in the transfer of retinol from hepatocytes to hepatic stellate cells via a RBP receptor STRA6. Vitamin A is then stored as retinyl ester in cytoplasmic fat droplets in stellate cells. The present inventors disclosed that albumin is endogenously expressed in the stellate cells and involved in the formation of vitamin A-containing fat droplets, inhibiting stellate cell activation. The forced expression of albumin led to the phenotypic conversion from activated myofibroblast-like cells to quiescent fat-storing phenotype. (Non-Patent Document 1: Kim N, Yoo W, Lee J, Kim H, Lee H, Kim Y, Kim D, Oh J.* (2009) Formation of vitamin A fat droplets in pancreatic stellate cells requires albumin. Gut 58(10), 1382-90.; Non-Patent Document 2: Kim N, Choi S, Lim C, Lee H, Oh J. (2010) Albumin mediates PPAR-g and C/EBP-a-induced phenotypic changes in pancreatic stellate cells. Biochem. Biophys. Res. Commun. 391(1), 640-44.)